Diagnostic outcome of whole exome sequencing in Hong Kong familes with autism spectrum disorder

Abstract

Background: Autism spectrum disorder (ASD) is characterized by deficit in social communication and restricted repetitive behaviour or interest. While it is known that common variants and copy number variations contribute significantly to the pathogenesis of ASD, rare de novo single nucleotide variants are known to cause ASD in some of the cases. Currently, the mutational spectrum of ASD in Southern Chinese is understudied. We aimed at studying the diagnostic outcome of whole exome sequencing (WES) in Hong Kong families with ASD. Methods: We recruited subjects diagnosed with ASD based on DSM IV-TR or DSM-V criteria and their asymptomatic parents at Duchess of Kent Children's Hospital Child Assessment Centre to this study. WES was performed at Icahn School of Medicine at Mount Sinai as a part of the Autism Sequencing Consortium international collaboration. We performed sample-level and variant-level quality control using GATK-VQSR, KGGSeq and PLINK. De novo variants were called using customised bioinformatics pipeline with triodenovo and confirmed by manual inspection using IGV. Variants were prioritized based on population frequency (gnomAD frequency ≤ 1%) and ASD gene list curated by literature search. Phenotype-based variant prioritization was performed using text-mining algorithm VarElect in cases with additional phenotype or dysmorphism. The pathogenicity of variants was determined using ACMG guideline. Pathogenic mutations were confirmed using Sanger Sequencing. Results: We recruited 329 subjects in this study, of which 100 probands originated from trio or multiplex families and 229 subjects were singleton. Nine pathogenic/ likely pathogenic variants were identified in 8 cases (one proband was found to harbour both NSD1 and CHD7 mutations). Disease-causing mutation were identified in overgrowth-related genes (NSD1, PPP2R5D, PTEN, EZH2), multiplecongenital- anomalies-related genes (CREBBP, CHD7), neurodevelopmental-disorder-related genes (DEAF1, GRIN2B) and hearing-loss-related gene (WFS1). 6/9 of the variants were de novo while the inheritance of the remaining cases cannot be determined due to the lack of parental samples. The overall diagnostic yield was 2.5% while the diagnostic yield of trio/multiplex cases was 5.3%. Conclusion: Despite having relatively low diagnostic yield, WES still identifies pathogenic mutations in a small but significant proportion of ASD families. Case-based analysis also highlights phenotype expansion of ASD as clinical genetics transit into the era of genotype-guided practice. Pathogenic variants identified in syndromic ASD genes were found to present as non-syndromic ASD.